| First Author | Reich N | Year | 2010 |
| Journal | Arthritis Rheum | Volume | 62 |
| Issue | 1 | Pages | 280-90 |
| PubMed ID | 20039427 | Mgi Jnum | J:243844 |
| Mgi Id | MGI:5912623 | Doi | 10.1002/art.25056 |
| Citation | Reich N, et al. (2010) The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis Rheum 62(1):280-90 |
| abstractText | OBJECTIVE: Fra-2 belongs to the activator protein 1 family of transcription factors. Mice transgenic for Fra-2 develop a systemic fibrotic disease with vascular manifestations similar to those of systemic sclerosis (SSc). The aim of the present study was to investigate whether Fra-2 plays a role in the pathogenesis of SSc and to identify the molecular mechanisms by which Fra-2 induces fibrosis. METHODS: Dermal thickness and the number of myofibroblasts were determined in skin sections from Fra-2-transgenic and wild-type mice. The expression of Fra-2 in SSc patients and in animal models of SSc was analyzed by real-time polymerase chain reaction and immunohistochemistry. Fra-2, transforming growth factor beta (TGFbeta), and ERK signaling in SSc fibroblasts were inhibited using small interfering RNA, neutralizing antibodies, and small-molecule inhibitors. RESULTS: Fra-2-transgenic mice developed a skin fibrosis with increases in dermal thickness and increased myofibroblast differentiation starting at age 12 weeks. The expression of Fra-2 was up-regulated in SSc patients and in different mouse models of SSc. Stimulation with TGFbeta and platelet-derived growth factor (PDGF) significantly increased the expression of Fra-2 in SSc fibroblasts and induced DNA binding of Fra-2 in an ERK-dependent manner. Knockdown of Fra-2 potently reduced the stimulatory effects of TGFbeta and PDGF and decreased the release of collagen from SSc fibroblasts. CONCLUSION: We demonstrate that Fra-2 is overexpressed in SSc and acts as a novel downstream mediator of the profibrotic effects of TGFbeta and PDGF. Since transgenic overexpression of Fra-2 causes not only fibrosis but also vascular disease, Fra-2 might be an interesting novel candidate for molecular-targeted therapies for SSc. |
